The goal of the Gastrointestinal Malignancies Program (Gl Program) is to unravel the pathogenesis and pathophysiology of Gl cancers, study genetic and environmental risk factors, and design and implement novel strategies for diagnosis, treatment, and prevention. The Gl Program emerged from developing program status in 2003 after it had acquired sufficient organizational, investigative, and clinical depth to be reviewed as a CCSG Program in 2005. At the 2005 CCSG review, the Program received an Outstanding merit score and Approval [was] recommended with an outstanding level of enthusiasm. The Program has generated a culture of inter-institutional communication and collaboration that has brought together 83 basic, translational, clinical and population science investigators representing 12 departments of HMS and HSPH, and seven DF/HCC institutions, and has armed these investigators with enabling Cores. In the current budget year, Program members generated $13.7 million (total costs) in peer-reviewed grant support, with $11.5 million in funding from the NCI, and have published 1,272 papers (26% intra-programmatic, 50% interprogrammatic, and 32% inter-institutional) in the current project period (2006 to 2010). Given the complexity and heterogeneity of gastrointestinal malignancies, the Program has elected to emphasize its efforts on colorectal and pancreatic cancers, two of the four leading causes of cancer-related death in the Unites States. The Specific Aims of the Program are to: 1) utilize existing and emerging genome-scale and computational technologies to integrate multi-dimensional analysis of the somatic genetic and genomic alterations present in colorectal and pancreatic cancers, applying the ensuing knowledge to define key events that drive tumorigenesis, disease progression and drug response; 2) utilize genetic model systems to define genetic lesions that drive colorectal and pancreatic tumorigenesis; 3) determine whether polymorphic variation in the aforementioned genes increase risk of these cancers; 4) undertake targeted clinical trials utilizing novel endpoint assessment and imaging based upon the findings in Aims 1-3; and 5) determine the effectiveness of these interventions by evaluating patient outcomes. During the next project period, there will be a concurrent intensification of efforts on the other gastrointestinal malignancies, including hepatobililary cancers, esophagogastric cancers and neuroendocrine tumors.